SUMMARY Influenza A virus (IAV) is a significant threat to human health, affecting ~15% of the world's population annually. Most people who develop IAV recover in less than 2 weeks. However, a number of infected patients become critically ill and require intensive care. A subset of these patients exhibit severe progressive respiratory failure, often associated with multi-organ failure, and/or marked worsening of underlying airways disease and death. Epidemiological studies on IAV-associated deaths in Utah over the past 100 years provide strong evidence of host genetics as a risk factor. In vivo genetic studies using classical inbred strains of laboratory mice have contributed to our understanding of IAV pathogenesis and disease severity. However, as a consequence of undergoing extensive selection and domestication before and during inbreeding, classical inbred laboratory strains have a serious genetic limitation compared to human populations; they do not exhibit the same degree of genetic variation. The limited genetic diversity which distinguishes classical inbred laboratory strains used to study the genetics of IAV in vivo can be overcome by incorporating into the experimental design inbred wild-derived strains whose genetic diversity more accurately reflects the greater evolutionarily selected genetic diversity seen in humans. With respect to IAV, this is exemplified by the identification of functional Mx1 alleles segregating among inbred wild-derived stains that are quantitatively distinct, and exhibit background dependent epistasis. Taken together, this suggests that inbred wild-derived strains such as PWD and CAST (PWD; M. mus musculus and CAST; M. mus castaneus were separated ~0.8 Myr ago from each other, and from M. mus domesticus, the ancestry from which most classical inbred laboratory strains derived) may possess unique IAV-quantitative trait loci (IAV-QTL) that contribute to disease susceptibility and resistance as a function of either direct viral cytopathicity and/or immunopathologic damage. To test this hypothesis we will pursue two specific aims. In Specific Aim 1 we will perform genome-wide physical mapping using B6-ChrPWD and B6-ChrCAST consomic and conplastic strains of mice, which cover all 19 autosomes, X and Y chromosomes, and mitochondrial genome, to identify novel IAV-QTL underling susceptibility and/or resistance to IAV. In Specific Aim 2 we will determine the relative contribution that PWD and CAST IAV-QTL play in survival as a function of direct viral cytopathicity vs. immunopathologic damage.